There is an urgent need to find simple and affordable intervention strategies to reduce HIV transmission through breast-feeding in developing countries. Until an effective vaccine is found, chemoprophylaxis throughout the period of breast-feeding may be the most effective strategy. However, if we aim to maintain systemic antiviral drug levels, the price associated with prolonged administration and the risk of toxicity are severe limitations. We hypothesize that topical (oral) administration of very low doses of the antiviral drug tenofovir, which is rapidly taken up by cells, may result in mucosal intracellular drug levels that are sufficient to confer protection of the initial target cells against viral infection. To test this hypothesis, we propose to use the simian immunodeficiency virus (SIV)-infant macaque model of pediatric HIV infection. We recently demonstrated that infant macaques can be infected by repeatedly feeding them small amounts of SIV; accordingly, this animal model mimics the multiple low-dose exposure to virus that occurs during breast-feeding. In the proposed study, groups of 1 -month-old infant macaques will be exposed orally three times per day to low doses of SIV. One group will receive topical tenofovir prodrug solution, while the other groups will receive systemic tenofovir or will be placebo-treated. Animals will be monitored closely for the detection of virus or antiviral immune responses. If topical tenofovir administration were effective, then this simple strategy would be highly affordable for developing countries.